Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. A stroke, or cerebrovascular accident (CVA), is an acute cerebral circulation disorder, which can quickly lead to localized or diffused brain impairment in clinical events. Existing drugs for treating acute cerebral ischemic stroke can be divided into two categories: drugs that improve cerebral blood flow and neuroprotective drugs.
The delivery effectiveness is critical in the treatment of acute ischemic stroke. Neuroprotective drugs have various species. Over the past two decades, many investigators in different countries have spent billions of dollars on the development of neuroprotective drug species according to the mechanism of neuronal damage after cerebral ischemia at a cellular or molecular level. Since the 1950's, CDPC has been researched as a neuroprotective drug. The Takeda pharmaceutical company from Japan first successfully developed Nicholin (citicoline) to cure the disturbance of consciousness. In 2002, Davalos et al. analyzed the effect of oral CDPC treatment of ischemic stroke by evidence based on clinical trials. In 2005, Hurtado and others made a model of focal brain ischemia using adult male Fischer rats, then injected CDPC into the abdominal cavity of the Fischer rats and blocked the middle cerebral artery one hour after the injection. Hurtado's results demonstrate that injecting CDPC with different dosages (e.g., 0.5 g/kg, 1 g/kg and 2 g/kg) can reduce infarct size of the neostriatum. According to the study of Hurtado in 2008, comparing to the control group, 48 hour-brain infarct size can be reduced significantly if 2 g/kg of CDPC are injected into the abdominal cavity of Fischer rats four hours after embolism caused by focal brain ischemia. Clinical research and animal experiments have confirmed that CDPC has a significant neuroprotective function. Mechanistic studies also show that CDPC plays a role in protecting the brain from ischemia and treating injury mainly through stabilizing the cell membrane, suppressing the release of free fatty acid, reducing free radical generation and inhibiting cell apoptosis. The United States is currently conducting Phase III clinical trials for the treatment of stroke by oral administration of CDPC, but the treatment effect is not satisfactory.
It is generally believed that the unsatisfactory result is associated with the blood-brain barrier (BBB) of brain tissue. The BBB protects the brain micro-environment from the outside environment, but at the same time, the BBB also stops most neuroprotective drugs from entering. Cerebrovascular blood volume accounts for only 3% of the brain volume, and in a cerebral ischemic stroke the local blood flow decreases or even stops. Therefore, the conventional oral or intravenous delivery methods may not be able to reach the lesion.
In addition, it is difficult for a CDPC molecule, which has a strong polarity, to permeate the BBB. Increasing the dosage can improve the CDPC concentration in brain tissue, but it may also increase adverse effects of the CDPC.
In 1994, Bobo developed the concept of drug delivery via brain extracellular space (ECS) for treating encephalopathy. His work focused on macromolecular drugs which are driven by pressure, then diffused in the ECS and distributed to the target region of the brain. Currently most of the neuroprotective drugs are small molecule compounds less than 1,000 daltons, which have no successful reports on treating stroke via ECS.